Pyruvate augments calcium transients and cell shortening in rat ventricular myocytes.
Pyruvate has been shown to be a metabolic inotrope in the myocardium. In millimolar concentrations, it has been shown to increase both myocardial phosphorylation potential and the cytosolic [NAD+]-to-[NADH] ratio. To determine if changes in these parameters can alter intracellular Ca2+ concentration ([Ca2+]i) and hence contractile function, Ca2+ transients and cell shortening (CS) were measured in isolated rat ventricular myocytes superfused with a physiological N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid buffer (11 mmol/l glucose) with and without additional pyruvate, L-lactate, acetate, or isoproterenol. The addition of 5 mmol/l pyruvate resulted in a 33% increase in CS and a 39% increase in systolic [Ca2+]i. These pyruvate effects were 70% of those observed with 100 nmol/l isoproterenol. The mitochondrial monocarboxylate transport inhibitor alpha-cyano-4-hydroxycinnamate (250 mumol/l) strongly inhibited pyruvate inotropy, suggesting a substantial obligatory coupling between pyruvate inotropism and its oxidation by the mitochondria. A possible role of the cytosolic [NAD+]-to-[NADH] ratio was assessed by comparing the effects of 20 mmol/l L-lactate to those of equimolar pyruvate. In contrast to 20 mmol/l pyruvate, excess L-lactate failed to appreciably increase CS or systolic [Ca2+]i. The findings imply that, at levels substantially above 5 mmol/l, a portion of pyruvate inotropism might be due to extreme cytosolic [NAD+]-to-[NADH] ratios. This study is the first evidence that augmented [Ca2+]i transients are most likely the mechanism of cardiac pyruvate inotropism.
Martin
B J
BJ
Division of Cardiothoracic Surgery, University of Wisconsin School of Medicine, Madison 53792-0001, USA.
Valdivia
H H
HH
Bünger
R
R
Lasley
R D
RD
Mentzer
R M
RM
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D006321:Heart / Q000502:physiology*; D006352:Heart Ventricles; D019344:Lactic Acid / Q000494:pharmacology; D008297:Male; D008929:Mitochondria, Heart / Q000378:metabolism; D008955:Models, Cardiovascular; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D009243:NAD / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D010766:Phosphorylation; D019289:Pyruvic Acid / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
D009243:NAD; D019344:Lactic Acid; D009249:NADP; D019289:Pyruvic Acid; D005947:Glucose; D002118:Calcium